Association of Cardiopulmonary Hemodynamics and Mortality in Veterans With Liver Cirrhosis: A Retrospective Cohort Study

Background Portopulmonary hypertension (PoPH), associated with increased mortality, can limit treatment options for liver diseases. Data on the continuum of clinical risk related to cardiopulmonary hemodynamics in PoPH are lacking. Methods and Results As part of the United States national Veterans Affairs Clinical Assessment, Reporting, and Tracking database, we performed a retrospective cohort study of adults with cirrhosis undergoing right heart catheterization between October 1, 2017, and September 30, 2022. Pulmonary hypertension (mean pulmonary arterial pressure [mPAP] >20 mm Hg without PoPH) and PoPH (mPAP >20 mm Hg+pulmonary artery wedge pressure ≤15 mm Hg+pulmonary vascular resistance ≥3 WU) were defined by right heart catheterization hemodynamics. Multivariable Cox proportional hazards using natural splines for hemodynamic variables were used to evaluate the association between cardiopulmonary hemodynamics and mortality following right heart catheterization. A total of 4409 patients were included in the final analysis, predominantly men (96.3%), with a mean age of 68.5 years. Pulmonary hypertension and PoPH were observed in 71.6% and 10.2% of the cohort, respectively. Compared with a reference cardiac index of 2.5 L/min per m2, the hazard for mortality increased progressively with decreasing cardiac index, even after adjustment for mPAP and pulmonary vascular resistance. The minority of patients with PoPH (N=65, 14.5%) were prescribed pulmonary vasodilator therapy. Conclusions These data suggest that pulmonary hypertension and PoPH are prevalent in veterans with chronic liver disease, but low use of targeted PoPH therapy persists. Cardiac function discriminated mortality risk across a wide range of mPAP and pulmonary vascular resistance values and may diagnose and clarify prognosis in this patient population.


Medication Definitions
Prescriptions for endothelin receptor antagonist therapy included bosentan, ambrisentan, or macitentan.
Prescriptions for soluble guanylate cyclase stimulator therapy included riociguat.Prescriptions for prostacyclin pathway modulator therapy included selexipag, epoprostenol, or treprostinil.Prescriptions for phosphodiesterase-5 inhibitor therapy included sildenafil or tadalafil.Outpatient prescription fill of systemic anticoagulation therapy included warfarin, heparin, rivaroxaban, apixiban, edoxaban, dabigatran, or betrixaban.Outpatient prescription fill of liver cirrhosis therapy included rifaximin, propranolol, nadolol, lactulose, or ursodiol.Outpatient prescription fill of beta-adrenergic receptor antagonist therapy included carvedilol, metoprolol, bisoprolol, propranolol, and labetalol.The reference mean pulmonary arterial pressure (mPAP) is 10 mmHg.The reference pulmonary vascular resistance (PVR) is 1 Wood Units.The reference pulmonary artery wedge pressure (PAWP) is 10 mmHg.The reference cardiac index (CI) value is 2.5 L/min/m 2 .Multivariable models were adjusted for age, sex, race, ethnicity, Veteran's Administration procedural site, MELD-XI, and comorbidities

Figure S3
The association between PAWP and mortality in the study cohort Adjusted hazard ratio for all-cause mortality at 1-and 3-years following right heart catheterization as a function of pulmonary artery wedge pressure (PAWP).Hazard ratios (solid line) with 95% confidence intervals (dashed bands) are plotted for PAWP relative to a reference value of 10 mmHg (vertical dotted line).The hazard ratios on the y-axis are demarcated by a logarithmic scale, and a hazard ratio of 1 is depicted by a horizontal dotted line.A rugplot showing the distribution of PAWP values is displayed directly above the x-axis.Multivariable models adjusted for age, sex, race, ethnicity, Veteran's Administration procedural site, MELD-XI, and comorbidities

Figure S4
Figure S4 Kaplan Meier analysis for survival probability dichotomized by CI

Figure S5
Figure S5 Kaplan Meier analysis for survival probability in PoPH patients dichotomized by PAH-targeted therapy

Table S2 : Summary of hazard ratios for adjusted models between cardiopulmonary hemodynamic variables and all-cause mortality Clinical Variable 1 YEAR MORTALITY 3 YEAR MORTALITY Adjusted Hazard Ratio 95% Confidence Interval p-value Adjusted Hazard Ratio 95% Confidence Interval p-value mPAP (mmHg) 28
The reference mean pulmonary arterial pressure (mPAP) is 10 mmHg.The reference pulmonary vascular resistance (PVR) is 1 Wood Units.The reference pulmonary artery wedge pressure (PAWP) is 10 mmHg.Multivariable models were adjusted for age, sex, race, ethnicity, Veteran's Administration procedural site, MELD-XI, and comorbidities

Table S3 : Summary of hazard ratios for adjusted models between cardiac index and all-cause mortality
The reference cardiac index (CI) value is 2.5 L/min/m 2 .Multivariable models were adjusted for age, sex, race, ethnicity, Veteran's Administration procedural site, MELD-XI, and comorbidities.

Table S4 : Summary of hazard ratios for adjusted models between cardiac index and all-cause mortality, further adjusted for mPAP and PAWP
The reference cardiac index (CI) value is 2.5 L/min/m 2 .Multivariable models were adjusted for age, sex, race, ethnicity, Veteran's Administration procedural site, MELD-XI, and comorbidities.

Table S5 : Summary of hazard ratios for unadjusted and adjusted models between cardiopulmonary hemodynamics and 3-year mortality
The reference mean pulmonary arterial pressure (mPAP) is 10 mmHg.The reference pulmonary vascular resistance (PVR) is 1 Wood Units.The reference pulmonary artery wedge pressure (PAWP) is 10 mmHg.The reference cardiac index (CI) value is 2.5 L/min/m 2 .Multivariable models were adjusted for age, sex, race, ethnicity, Veteran's Administration procedural site, MELD-XI, and comorbidities.

Table S7 : Summary of hazard ratios for adjusted models between cardiopulmonary hemodynamics and all-cause mortality for patients with MELD- XI <12
The reference mean pulmonary arterial pressure (mPAP) is 10 mmHg.The reference pulmonary vascular resistance (PVR) is 1 Wood Units.The reference pulmonary artery wedge pressure (PAWP) is 10 mmHg.The reference cardiac index (CI) value is 2.5 L/min/m 2 .Multivariable models were adjusted for age, sex, race, ethnicity, Veteran's Administration procedural site, MELD-XI, and comorbidities